NgR蛋白在胶质细胞中的表达研究
摘要
中枢神经系统(central nervous system,CNS)区别于周围神经系统(peripheral nervous system,PNS)很重要的一点在于CNS的轴突损伤后不能再生,而PNS的轴突则可以。CNS不同于PNS的不利环境,尤其是其特有的髓鞘结构对神经再生起了很大的阻碍作用。人们从CNS髓鞘中提取纯化了多种抑制性蛋白质,称为髓鞘相关抑制因子(myelin associated inhibitory factors,MAIFs),主要包括Nogo-A,MAG(myelin associated glycoprotein)和OMgp(oligodendrocyte myelin glycoprotein);这些分子不同程度地引起生长锥塌陷,抑制轴突再生,而且都是通过同一个受体—NgR(Nogo-66 receptor)向胞内传递抑制信号,发挥作用。因此,NgR作为潜在的治疗CNS损伤的靶点,越来越为人们所关注。
NgR属于磷脂酰肌醇(Glycosylphosphatidyl nositol,GPI)锚定蛋白,含有8个富含亮氨酸的重复序列(Leucine Repeat Region,LRR),和与其高度同源的两个分子NgRH1和NgRH2同属NgR家族。NgR主要在脑高表达,也低水平表达于外周的心脏、肾脏等少数器官;在正常成年大鼠CNS,NgR主要分布在神经元以及髓鞘包绕的轴突上,MAIFs正是通过和神经元上的NgR结合产生抑制作用的。
最近,有证据提示NgR蛋白也分布于胶质细胞。我们实验室
One big difference existing between central nervous system (CNS) and peripheral nervous system (PNS) is that injuried axons of CNS could not regenerate any more while nerves in PNS could. The specific and unfriendly surroundings of CNS,especially CNS myelin,which is quite different from that of PNS,contribute a lot to the regeneration failure.Several inhibitory proteins have been extracted from CNS myelin. These proteins,which mainly refer to Nogo-A,MAG ( myelin associated glycoprotein) and OMgp (oligodendrocyte myelin glycoprotein),are recognized as MAIFs (myelin associated inhibitory factors).MAIFs cause growth cone collapse and block axonal sprouting,and they have been found to transmit signals intracellularly through binding the same receptor-NgR (Nogo-66 receptor) . Therefore, as a potent target of treating CNS injury,NgR is getting more and more attention.NgR is a GPI ( Glycosylphosphatidyl nositol) -linked cell surface protein ,boasting eight leucine repeat regions (LRR) . NgR and other two molecules-NgRH1 and NgRH2,which have high homology
with NgR,constitute the NgR family.NgR is expressed prodominantly in brain and only moderately in several other organs such as heart and kidney.In CNS of normal adult rat, NgR has been found widely distributed in many classes of neurons and presented through axons surrounded by myelin.And it is NgR on the neural surface that binds MAIFs and take inhibitory effect.Recently, evidence have been offered to suggest that NgR is also expressed in glial cells.Our previous study has showed through immunohistochemical staining and immuno-electron microscopy that in spinal cord and cerebellum of adult normal rat ,NgR is found in glial cells of neuropils.Xiao ZC and his colleagues in Singapore reported having detected NgR protein in human U87MG glioma cells.However,more detailed studies of NgR in glial cells are needed.Based on these findings,we attempted to investigate the expression and distribution of NgR in glial cells systemicly.Our main results are as following:1. Identification of reactivity and specificity of several NgR antibodies which recognize different epitopes. In Blots, AB5615、 sc-25659 and NgRPAb were all shown to react with NgR specifically, but not with its family members, NgRH1 or NgRH2. Double immunofluorescence staining with Flag and several NgR antibodies in Flag-NgR tansfected COS cells showed that, besides Ngr11-A, NgR antibodies can stain predominantly the plasma membrane and perinuclear organelles labeled by Flag antibody. By RT-PCR and Western blot, PC12 and C17.2 cells were confirmed to express mRNA and protein of NgR, then indirect immunofluorescence technique revealed intracellular localization of NgR protein in PC12, C17.2 and CGN cells.The results showed that all the NgR antibodies we used could react with NgR specifically. Different NgR antibodies behaved differently in Western blot and immunofluorescence staining.2. NgR is expressed in rat astrocytes.Specific NgR cDNA product could
NgR属于磷脂酰肌醇(Glycosylphosphatidyl nositol,GPI)锚定蛋白,含有8个富含亮氨酸的重复序列(Leucine Repeat Region,LRR),和与其高度同源的两个分子NgRH1和NgRH2同属NgR家族。NgR主要在脑高表达,也低水平表达于外周的心脏、肾脏等少数器官;在正常成年大鼠CNS,NgR主要分布在神经元以及髓鞘包绕的轴突上,MAIFs正是通过和神经元上的NgR结合产生抑制作用的。
最近,有证据提示NgR蛋白也分布于胶质细胞。我们实验室
One big difference existing between central nervous system (CNS) and peripheral nervous system (PNS) is that injuried axons of CNS could not regenerate any more while nerves in PNS could. The specific and unfriendly surroundings of CNS,especially CNS myelin,which is quite different from that of PNS,contribute a lot to the regeneration failure.Several inhibitory proteins have been extracted from CNS myelin. These proteins,which mainly refer to Nogo-A,MAG ( myelin associated glycoprotein) and OMgp (oligodendrocyte myelin glycoprotein),are recognized as MAIFs (myelin associated inhibitory factors).MAIFs cause growth cone collapse and block axonal sprouting,and they have been found to transmit signals intracellularly through binding the same receptor-NgR (Nogo-66 receptor) . Therefore, as a potent target of treating CNS injury,NgR is getting more and more attention.NgR is a GPI ( Glycosylphosphatidyl nositol) -linked cell surface protein ,boasting eight leucine repeat regions (LRR) . NgR and other two molecules-NgRH1 and NgRH2,which have high homology
with NgR,constitute the NgR family.NgR is expressed prodominantly in brain and only moderately in several other organs such as heart and kidney.In CNS of normal adult rat, NgR has been found widely distributed in many classes of neurons and presented through axons surrounded by myelin.And it is NgR on the neural surface that binds MAIFs and take inhibitory effect.Recently, evidence have been offered to suggest that NgR is also expressed in glial cells.Our previous study has showed through immunohistochemical staining and immuno-electron microscopy that in spinal cord and cerebellum of adult normal rat ,NgR is found in glial cells of neuropils.Xiao ZC and his colleagues in Singapore reported having detected NgR protein in human U87MG glioma cells.However,more detailed studies of NgR in glial cells are needed.Based on these findings,we attempted to investigate the expression and distribution of NgR in glial cells systemicly.Our main results are as following:1. Identification of reactivity and specificity of several NgR antibodies which recognize different epitopes. In Blots, AB5615、 sc-25659 and NgRPAb were all shown to react with NgR specifically, but not with its family members, NgRH1 or NgRH2. Double immunofluorescence staining with Flag and several NgR antibodies in Flag-NgR tansfected COS cells showed that, besides Ngr11-A, NgR antibodies can stain predominantly the plasma membrane and perinuclear organelles labeled by Flag antibody. By RT-PCR and Western blot, PC12 and C17.2 cells were confirmed to express mRNA and protein of NgR, then indirect immunofluorescence technique revealed intracellular localization of NgR protein in PC12, C17.2 and CGN cells.The results showed that all the NgR antibodies we used could react with NgR specifically. Different NgR antibodies behaved differently in Western blot and immunofluorescence staining.2. NgR is expressed in rat astrocytes.Specific NgR cDNA product could
引文
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[2] Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature,2000,403:434-439.
[3] Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie G, Michalovich D, Simmons DL, Walsh FS. Inhibitor of neurite outgrowth in humans. Nature,2000,403:383-384.
[4] McKerracher L, David S, Jackson DL, Kottis V, Dunn RJ, Braun PE. Identification of myelin-associated glycoprotein as a major myelin derived inhibitor of neurite growth. Neuron, 1994,13:805-811.
[5] Mukhopadhyay G,Doherty P, Walsh FS, Crocker PR, Filbin MT. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron, 1994,13:757-767.
[6] Wang KC., Koprivica V., Kim J. A., Sivasankaran R., Guo Y., Neve R. L. & HE Z. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature, 2002a,417:941-944.
[7] Fournier AE, GrandPre T, Strittmatter SM. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 2001.409.341-346.
[8] Domeniconi M, Cao Z., Spenner T., Sivasankaran R., Wang K., Nikulina E, Kimura N, Cai H., Deng K., Gao Y., HE Z. & Filbin M. Myelin-associated glycoprotein interacts with the nogo66 receptor to inhibit neurite outgrowth. Neuron,2002,35:283-290.
[9] Liu BP, Fournier A., Grandpre T & Strittmatter S M. Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science, 2002,97:1190-1193.
[10] Barton WA, Liu BP, Tzvetkova D, Jeffrey PD, Fournier AE, Sah D, Cate R, Strittmatter SM, Nikolov DB. Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins. EMBO J,2003,22.:3291-3302.
[11] He XL, Bazan JF, McDermott. G, Park JB, Wang K, Tessier-Lavigne M, He Z, Garcia KC. Structure of the Nogo receptor ectodomain: a recognition module implicated in myelin inhibition. Neuron,2003,38:177-185.
[12] Wang KC, Kim JA, Sivasankaran R, Segal R, He Z. p75 interacts with the Nogo receptor as a coreceptor for Nogo, MAG and OMgp. Nature,2002b,420:74-78.
[13] Fournier AE, Gould GC, Liu BP, Strittmatter SM, Truncated soluble Nogo receptor binds Nogo-66 and blocks inhibition of axon growth by myelin, J. Neurosci,2002,22:8876-8883.
[14]Pignot V, Hein AE, Barske C, Wiessner C, Walmsley AR, Kaupmann K, Mayeur H,Sommer B, Mir AK and Frentzel S.Characterization of two novel proteins, NgRHl and NgRH2, structurally and biochemically homologous to the Nogo-66 receptor. Journal of Neurochemistry,2003,85: 717-728.
[15]Walmsley AR, McCombie G, Neumann U, Marcellin D, Hillenbrand R, Mir AK, Frentzel S. Zinc metalloproteinase-mediated cleavage of the human Nogo-66 receptor. J Cell Sci,2004,117:4591-4602.
[16]Hunt D, Coffin RS, Anderson PN, The Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review. J Neurocytol,2002b,31 :93-120.
[17]Liao H, Duka T, Teng FY, Sun L, Bu WY, Ahmed S, Tang BL, Xiao ZC.Nogo-66 and myelin-associated glycoprotein (MAG) inhibit the adhesion and migration of Nogo-66 receptor expressing human glioma cells. .J Neurochem.2004,90:1156-1162.
[18]Liu X, Liu YY, Jin WL, et al. Nogo-66-receptor at cerebellar cortical glia gap junctions in the rat. Neurosignals,in press.
[19]Hunt D, M.R.J, Campbell G, Coffin RS, Anderson PN. Nogo receptor mRNA expression in intact and regenerating CNS neurons. Molecular and Cellular Neuroscience,2002a,20:537-552.
[20]Josephson A, Trifunovski A , Widmer HR, Widenfalk J, Olson L, Spenger C Nogo-receptor gene activity: Cellular localization and developmental regulation of mRNA in mice and humans. Journal of Comparative Neurology,2002,453:292-304.
[21]Wang XX, Chun SJ, Treloar H, Vartanian T, Greer CA, Strittmatter SM. Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon- myelin and synaptic contact. Journal of Neuroscience,2002,22:5505-5515.
[22]Grandpre T, Li S, Strittmatter SM. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature,2002, 417:547-551.
[23]Li S, Strittmatter SM.Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury. J Neurosci,2003,23:4219-4127.
[24]Fischer, D., He, Z., Benowitz, L.I., Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state. J. Neurosci, 2004,24:1646- 1651.
[25]Shuxin Li, Ji-Eun Kim, Stephane Budel.Thomas G. Hampton.c and Stephen M. Strittmatter,T Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury. Mol. Cell. Neurosci,2005,in press.
[26]Binhai Zheng, Jasvinder Atwal, Carole Ho, Lauren Case, Xiao-lin He, K. Christopher Garcia, Oswald Steward_,and Marc Tessier-Lavigne. Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo. PNAS ,2005 ,102:1205-1210
[27]Kim, J.E., Liu, B.P., Park, J.H., Strittmatter, S.M., Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury. Neuron,2004,44:439- 451.
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